4,4-(disubstituted)cyclohexan-1-carboxylate monomers and related compounds

ABSTRACT

The present invention relates to novel 4,4-(disubstituted)cyclohexan-1-carboxylate monomers and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).

This application is a 371 of PCT/US95/16857 filed Dec. 21, 1995.

FIELD OF INVENTION

The present invention relates to novel4,4-(disubstituted)cyclohexan-1-carboxylate monomers and relatedcompounds pharmaceutical compositions containing these compounds, andtheir use in treating allergic and inflammatory diseases and forinhibiting the production of Tumor Necrosis Factor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof the disease. Thus, it seems unlikely that eliminating the effects ofa single mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the "mediator approach" is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

One such way is by elevating levels of cAMP (adenosine cyclic3',5'-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973!. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺² -ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. Torphy,"Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents" in New Drugs for Asthma, Barnes, ed. IBC Technical ServicesLtd., 1989!. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of-monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC(AIDS related complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis, in addition to a number ofautoimmune diseases, such as multiple sclerosis, autoimmune diabetes andsystemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell-mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after Tcell activation and such virus protein expression and/or replication ismediated or maintained by such T cell activation. Once an activated Tlymphocyte is infected with HIV, the T lymphocyte must continue to bemaintained in an activated state to permit HIV gene expression and/orHIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediatedHIV protein expression and/or virus replication by playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity such as by inhibition of cytokine production, notablyTNF, in an HIV-infected individual aids in limiting the maintenance of Tcell activation, thereby reducing the progression of HIV infectivity topreviously uninfected cells which results in a slowing or elimination ofthe progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells. See Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, Vol. 57, 1989!. Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophagesSee Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990!, therefore,inhibition of monokine production or activity aids in limiting HIVprogression as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells. See Riipi et al., Infectionand Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal ofInfectious Diseases, 164:389-95, 1991. See also Wasan et al.,Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Lukeet al., Journal of Infectious Diseases, 162:211-214, 1990!.

The ability to control the adverse effects of TNF is furthered by theuse of the compounds which inhibit TNF in mammals who are in need ofsuch use. There remains a need for compounds which are useful intreating TNF-mediated disease states which are exacerbated or caused bythe excessive and/or unregulated production of TNF.

SUMMARY OF THE INVENTION

In a first aspect this invention relates to compounds of formula (Ia)and (Ib): ##STR1## wherein: R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆,--(CR₄ R₅)_(n) C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆,or --(CR₄ R₅)_(r) R₆ wherein the alkyl moieties unsubstituted orsubstituted with one or more halogens;

m is 0 to 2;

n is 0 to 4;

r is 0 to 6;

R₄ and R₅ are independently selected hydrogen or C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ allkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl,indenyl, C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl,tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C₃₋₆ cycloalkyl, or a C₄₋₆cycloalkyl containing one or two unsaturated bonds, wherein thecycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1to 3 methyl groups, one ethyl group, or an hydroxyl group;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅)_(n)O(CR₄ R₅)_(m) R₆ ;

X is YR₂, fluorine, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m) ';

m' is 0, 1, or 2;

X₂ is O or NR₈ ;

X₃ is hydrogen or X;

X₄ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈ R₈ ;

R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens;

s is 0 to 4;

W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynylof 2 to 6 carbon atoms;

R₃ is COOR₁₄, C(O)NR₄ R₁₄ or R₇ ;

Z is C(Y')R₁₄, C(O)OR₁₄, C(Y')NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈ NR₈ C(O)R₈, C(O)NR₈ NR₁₀ R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀ R₁₄,C(NR₁₄)NR₈ R₈, C(NCN)NR₁₀ R₁₄, C(NCN)SR₉, (2-, 4- or 5-imidazolyl), (3-,4- or 5-pyrazolyl), (4- or 5-triazolyl 1,2,3!), (3- or 5-triazolyl1,2,4!), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or5-isoxazolyl), (3- or 5-oxadiazolyl 1,2,4!), (2-oxadiazolyl 1,3,4!),(2-thiadiazolyl 1,3,4!), (2-, 4-, or 5-thiazolyl), (2-, 4-, or5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or5-imidazolidinyl); wherein all of the heterocylic ring systems areunsubstituted or substituted one or more times by R₁₄ ;

Y' is O or S;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is unsubstituted or substituted one or more times by methyl orethyl unsubstituted or substituted by 1-3 fluorines, --F, --Br, --Cl,--NO₂, --NR₁₀ R₁₁, --C(O)R₈, --CO₂ R₈, --O(CH₂)_(q) R₈, --CN, --C(O)NR₁₀R₁₁, --O(CH₂)_(q) C(O)NR₁₀ R₁₁, --O(CH₂)_(q) C(O)R₉, --NR₁₀ C(O)NR₁₀R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁,--C(NCN)NR₁₀ R₁₁, --C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁,--NR₁₀ S(O)₂ R₉, --S(O)_(m) 'R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀C(O)C(O)R₁₀, or R₁₃ ;

q is 0, 1, or 2;

R₁₂ is R₁₃, C₃ -C₇ cycloalkyl, or an unsubstituted or substituted arylor heteroaryl group selected from the group consisting of (2-, 3- or4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl),quinolinyl, naphthyl, and phenyl;

R₈ is hydrogen or R₉ ;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen, or C₁₋₄ alkyl unsubstituted or substituted by one tothree fluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may togetherwith the nitrogen form a 5 to 7 membered ring comprised of carbon orcarbon and one or more additional heteroatoms selected from O, N, or S;

R₁₃ is a substituted or unsubstituted heteroaryl group selected from thegroup consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl,triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl,isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R₁₃ is substitutedon R₁₂ or R₁₃ the rings are connected through a carbon atom and eachsecond R₁₃ ring may be unsubstituted or substituted by one or two C₁₋₂alkyl groups unsubstituted or substituted on the methyl with 1 to 3fluoro atoms;

R₁₄ is hydrogen or R₇ ; or when R₈ and R₁₄ are as NR₈ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring comprised ofcarbon or carbon and one or more additional heteroatoms selected from O,N, or S;

provided that:

(f) R₇ is not C₁₋₄ alkyl optionally substituted by one to threefluorines;

or the pharmaceutically acceptable salts thereof.

This invention also relates to the pharmaceutical compositionscomprising a compound of Formula (Ia) or (Ib) and a pharmaceuticallyacceptable carrier or diluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of Formula (Ia) or (Ib) asshown below.

The invention further provides a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofFormula (Ia) or (Ib) alone or mixtures thereof.

The invention also provides a method for the treatment of asthma whichcomprises administering to a mammal, including humans, in need thereof,an effective amount of a compound of Formula (Ia) or (Ib) alone or inadmixture.

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment, an effective TNF inhibiting amount ofa compound of Formula (Ia) or (Ib) alone or in admixture. This methodmay be used for the prophylactic treatment or prevention of certain TNFmediated disease states amenable thereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound ofFormula (Ia) or (Ib) alone or in admixture.

Compounds of Formula (I) are also useful in the treatment of additionalviral infections, where such viruses are sensitive to upregulation byTNF or will elicit TNF production in vivo.

In addition, compounds of Formulas (Ia) or (Ib) are also useful intreating yeast and fungal infections, where such yeast and fungi aresensitive to upregulation by TNF or will elicit TNF production in vivo.

DETAILED DESCRIPTION OF THE INVENTION

This invention also relates to a method of mediating or inhibiting theenzymatic activity (or catalytic activity) of PDE IV in a mammal in needthereof and to inhibiting the production of TNF in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of Formula (Ia) or (Ib).

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus and central nervous system disorders such asdepression and multi-infarct dementia.

The viruses contemplated for treatment herein are those that produce TNFas a result of infection, or those which are sensitive to inhibition,such as by decreased replication, directly or indirectly, by the TNFinhibitors of Formula (I). Such viruses include, but are not limited toHIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus andthe Herpes group of viruses, such as, but not limited to, Herpes zosterand Herpes simplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (Ia) or (Ib).

The compounds of this invention may also be used in association with theveterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of this invention are also useful in treating yeast andfungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of Formulas (Ia) or (Ib) may be administered in conjunctionwith other drugs of choice for systemic yeast and fungal infections.Drugs of choice for fungal infections, include but are not limited tothe class of compounds called the polymixins, such as Polymycin B, theclass of compounds called the imidazoles, such as clotrimazole,econazole, miconazole, and ketoconazole; the class of compounds calledthe triazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

The compounds of Formulas (Ia) or (Ib) may also be used for inhibitingand/or reducing the toxicity of an anti-fungal, anti-bacterial oranti-viral agent by administering an effective amount of a compound ofFormula (Ia) or (Ib) to a mammal in need of such treatment. Preferably,a compound of Formula (Ia) or (Ib) is administered for inhibiting orreducing the toxicity of the Amphotericin class of compounds, inparticular Amphotericin B.

The term "C₁₋₃ alkyl", "C₁₋₄ alkyl", "C₁₋₆ alkyl" or "alkyl" groups asused herein is meant to include both straight or branched chain radicalsof 1 to 10, unless the chain length is limited thereto, including, butnot limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, and the like.

"Alkenyl" means both straight or branched chain radicals of 1 to 6carbon lengths, unless the chain length is limited thereto, includingbut not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl, or3-methyl-2-propenyl.

The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbonatoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, orcyclohexyl.

"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ringor ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl,or naphthyl. Preferably the aryl is monocyclic, i.e, phenyl. The alkylchain is meant to include both straight or branched chain radicals of 1to 4 carbon atoms.

"Heteroaryl" means an aromatic ring system containing one or moreheteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl,pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.

"Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo.

"Inhibiting the production of IL-1" or "inhibiting the production ofTNF" means:

a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, ina human to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

The phrase "TNF mediated disease or disease states" means any and alldisease states in which TNF plays a role, either by production of TNFitself, or by TNF causing another cytokine to be released, such as butnot limited to IL-1 or IL-6. A disease state in which IL-1, for instanceis a major component, and whose production or action, is exacerbated orsecreted in response to TNF, would therefore be considered a diseasestate mediated by TNF. As TNF-β (also known as lymphotoxin) has closestructural homology with TNF-α (also known as cachectin), and since eachinduces similar biologic responses and binds to the same cellularreceptor, both TNF-α and TNF-β are inhibited by the compounds of thepresent invention and thus are herein referred to collectively as "TNF"unless specifically delineated otherwise. Preferably TNF-α is inhibited."Cytokine" means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them. The cytokine inhibited by the present invention foruse in the treatment of a HIV-infected human must be a cytokine which isimplicated in (a) the initiation and/or maintenance of T cell activationand/or activated T cell-mediated HIV gene expression and/or replication,and/or (b) any cytokine-mediated disease associated problem such ascachexia or muscle degeneration. Preferrably, this cytokine is TNF-α.

All of the compounds of Formulas (Ia) or (Ib) are useful in the methodof inhibiting the production of TNF, preferably by macrophages,monocytes or macrophages and monocytes, in a mammal, including humans,in need thereof. All of the compounds of Formulas (Ia) or (Ib) areuseful in the method of inhibiting or mediating the enzymatic orcatalytic activity of PDE IV and in treatment of disease states mediatedthereby.

Preferred compounds are as follows:

When R₁ is an alkyl substituted by 1 or more halogens, the halogens arepreferably fluorine and chlorine, more preferably a C₁₋₄ alkylsubstituted by 1 or more fluorines. The preferred halo-substituted alkylchain length is one or two carbons, and most preferred are the moieties--CF₃, --CH₂ F, --CHF₂, --CF₂ CHF₂, --CH₂ CF₃, and --CH₂ CHF₂. PreferredR₁ substitutents are CH₂ -cyclopropyl, CH₂ -C₅₋₆ cycloalkyl, C₄₋₆cycloalkyl with or without an hydroxyl group, C₇₋₁₁ polycycloalkyl, (3-or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkylunsubstituted or substituted by 1 or more fluorines, --(CH₂)₁₋₃C(O)O(CH₂)₀₋₂ CH₃, --(CH₂)₁₋₃ O(CH₂)₀₋₂ CH₃, and --(CH₂)₂₋₄ OH.

When the R₁ term is (CR₄ R₅), the R₄ and R₅ terms are independentlyhydrogen or alkyl. This allows for branching of the individual methyleneunits as (CR₄ R₅)_(n) or (CR₄ R₅)_(m) ; each repeating methylene unit isindependent of the other, e.g., (CR₄ R₅)_(n) wherein n is 2 can be --CH₂CH(--CH₃)--, for instance. The individual hydrogen atoms of therepeating methylene unit or the branching hydrocarbon can unsubstitutedor be substituted by fluorine independent of each other to yield, forinstance, the preferred R₁ substitutions, as noted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo 2.2.1!-heptyl,bicyclo 2.2.2!octyl, bicyclo 3.2.1!octyl, tricyclo 5.2.1.0²,6 !decyl,etc. additional examples of which are described in Saccamano et al., WO87/06576, published 5 Nov. 1987, whose disclosure is incorporated hereinby reference in its entirety.

W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, andwhere it is alkenyl or alkynyl, that one or two double or triple bondsbe present. It is most preferred that W be ethynyl or 1,3-butadiynyl.

Z is preferably C(O)R₁₄, C(O)OR₁₄, C(O)NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN,C(NOR₈)R₈, C(O)NR₈ NR₈ C(O)R₈, C(NR₈)NR₁₀ R₁₄, C(NCN)NR₁₀ R₁₄,C(NCN)SR₉, (1-, 4- or 5-{R₈ }-2-imidazolyl), (1-, 4- or 5-{R₈}-3-pyrazolyl), (1-, 2- or 5-{R₈ }-4-triazolyl 1,2,3!), (1-, 2-, 4- or5-{R₈ }-3-triazolyl 1,2,4!), (1- or 2-{R₈ }-5-tetrazolyl), (4- or 5-{R₈}-2-oxazolyl), (3- or 4-{R₈ }-5-isoxazolyl), (3-{R₈ }-5-oxadiazolyl1,2,4!), (5-{R₈ }-3-oxadiazolyl 1,2,4!), (5-{R₈ }-2-oxadiazolyl 1,3,4!),(5-{R₈ }-2-thiadiazolyl 1,3,4!), (4- or 5-{R₈ }-2-thiazolyl), (4- or5-{R₈ }-2-oxazolidinyl), (4- or 5-{R₈ }-2-thiazolidinyl),(1-, 4- or5-{R₈ }-2-imidazolidinyl); most preferred are those compounds whereinthe R₈ group of Z is R₄. Z is preferably C(O)R₁₄, C(O)OR₁₄, or C(O)NR₁₀R₁₄.

Preferred X groups are those wherein X is YR₂ and Y is oxygen. Thepreferred X₂ group is that wherein X₂ is oxygen. The preferred X₃ groupis that wherein X₃ is hydrogen. Preferred R₂ groups, where applicable,is a C₁₋₂ alkyl unsubstituted or substituted by 1 or more halogens. Thehalogen atoms are preferably fluorine and chlorine, more preferablyfluorine. More preferred R₂ groups are those wherein R₂ is methyl, orthe fluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a--CF₃, --CHF₂, or --CH₂ CHF₂ moiety. Most preferred are the --CHF₂ and--CH₃ moieties.

Preferred R₇ moieties include unsubstituted or substituted --(CH₂)₀₋₂(2-, 3- or 4-pyridyl), (CH₂)₁₋₂ (2-imidazolyl), (CH₂)₂ (4-morpholinyl),(CH₂)₂ (4-piperazinyl), (CH₂)₁₋₂ (2-thienyl), (CH₂)₁₋₂ (4-thiazolyl),unsubstituted or substituted pyrimidinyl, and substituted orunsubstituted (CH₂)₀₋₂ phenyl.

Preferred rings when R₁₀ and R₁₁ in the moiety --NR₁₀ R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringunsubstituted or containing at least one additional heteroatom selectedfrom O, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₈ and R₁₄ in the moiety --NR₈ R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringunsubstituted or containing at least one additional heteroatom selectedfrom O, N, or S include, but are not limited to 1-imidazolyl,1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl,morpholinyl, piperazinyl, and pyrrolyl. The respective rings may beadditionally substituted, where applicable, on an available nitrogen orcarbon by the moiety R₇ as described herein for Formula (I).Illustrations of such carbon substitutions include, but are not limitedto, 2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇)-2-tetrazolyl.Applicable nitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₈ R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl,4-(R₁₄)-1-piperazinyl, or 4-(R₁₅)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl 1,2,3!), (3- or 5-triazolyl 1,2,4!),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl 1,2,4!), (2-oxadiazolyl 1,3,4!), (2-thiadiazolyl 1,3,4!),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R₇ group is unsubstituted or substituted by a heterocyclic ringsuch as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be unsubstituted or substituted by R₈either on an available nitrogen or carbon atom, such as1-(R₈)-2-imidazolyl, 1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl,1-(R₈)-3-pyrazolyl, 1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl,1-(R₈)-4-triazolyl, or 1-(R₈)-5-triazolyl. Where applicable, the ringmay be substituted one or more times by R₈.

Preferred are those compounds of Formula (I) wherein R₁ is --CH₂-cyclopropyl, --CH₂ --C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl unsubstitutedor substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl),benzyl or --C₁₋₂ alkyl unsubstituted or substituted by 1 or morefluorines, and --(CH₂)₂₋₄ OH; R₂ is methyl or fluoro-substituted alkyl,W is ethynyl or 1,3-butadiynyl; R₃ is R₇ where R₇ is an unsubstituted orsubstituted aryl or heteroaryl ring, X is YR₂, and Z is OR₁₄, OR₁₅, NR₁₀R₁₄, or NR₁₄ C(O)R₉.

Most preferred are those compounds wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, 3-hydroxycyclopentyl, methyl or CF₂ F; X is YR₂ ; Y isoxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂ F or methyl, W isethynyl or 1,3-butadiynyl, and R₃ is a substituted or unsubstitutedpyrimidinyl ring.

Pharmaceutically acceptable salts of the instant compounds, where theycan be prepared, are also intended to be covered by this invention.These salts will be ones which are acceptable in their application to apharmaceutical use. By that it is meant that the salt will retain thebiological activity of the parent compound and the salt will not haveuntoward or deleterious effects in its application and use in treatingdiseases.

Pharmaceutically acceptable salts are prepared in a standard manner. Theparent compound, dissolved in a suitable solvent, is treated with anexcess of an organic or inorganic acid, in the case of acid additionsalts of a base, or an excess of organic or inorganic base where themolecule contains a COOH for example.

Pharmaceutical compositions of the present invention comprise apharmaceutical carrier or diluent and some amount of a compound of theinvention. The compound may be present in an amount to effect aphysiological response, or it may be present in a lesser amount suchthat the user will need to take two or more units of the composition toeffect the treatment intended. These compositions may be made up as asolid, liquid or in a gaseous form. Or one of these three forms may betransformed to another at the time of being administered such as when asolid is delivered by aerosol means, or when a liquid is delivered as aspray or aerosol.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the intended route of administration, forexample parenterally, topically, orally or by inhalation.

For topical administration the pharmaceutical composition will be in theform of a cream, ointment, liniment, lotion, pastes, aerosols, and dropssuitable for administration to the skin, eye, ear, or nose.

For parenteral administration the pharmaceutical composition will be inthe form of a sterile injectable liquid such as an ampule or an aqueousor non-aqueous liquid suspension.

For oral administration the pharmaceutical composition will be in theform of a tablet, capsule, powder, pellet, atroche, lozenge, syrup,liquid, or emulsion.

When the pharmaceutical composition is employed in the form of asolution or suspension, examples of appropriate pharmaceutical carriersor diluents include: for aqueous systems, water; for non-aqueoussystems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil,peanut oil, sesame oil, liquid parafins and mixtures thereof with water;for solid systems, lactose, kaolin and mannitol; and for aerosolsystems, dichlorodifluoromethane, chlorotrifluoroethane and compressedcarbon dioxide. Also, in addition to the pharmaceutical carrier ordiluent, the instant compositions may include other ingredients such asstabilizers, antioxidants, preservatives, lubricants, suspending agents,viscosity modifiers and the like, provided that the additionalingredients do not have a detrimental effect on the therapeutic actionof the instant compositions.

The pharmaceutical preparations thus described are made following theconventional techniques of the pharmaceutical chemist as appropriate tothe desired end product.

In these compositions, the amount of carrier or diluent will vary butpreferably will be the major proportion of a suspension or solution ofthe active ingredient. When the diluent is a solid it may be present inlesser, equal or greater amounts than the solid active ingredient.

Usually a compound of the invention is administered to a subject in acomposition comprising a nontoxic amount sufficient to produce aninhibition of the symptoms of a disease in which leukotrienes are afactor. Topical formulations will contain between about 0.01 to 5.0% byweight of the active ingredient and will be applied as required as apreventative or curative agent to the affected area. When employed as anoral, or other ingested or injected regimen, the dosage of thecomposition is selected from the range of from 50 mg to 1000 mg ofactive ingredient for each administration. For convenience, equal doseswill be administered 1 to 5 times daily with the daily dosage regimenbeing selected from about 50 mg to about 5000 mg.

No unacceptable toxicological effects are expected when these compoundsare administered in accordance with the present invention.

METHODS OF PREPARATION Synthetic Scheme(s) With Textual Description

Compounds of Formulas (Ia) or (Ib) may be prepared by the processesdisclosed herein which comprise reacting a terminal acetylene, wherein Zand X₄ represent Z and X₄ as defined above or a group convertible to Zand X₄, as, e.g., compound 1-Scheme 1, with an appropriate halide, R₃ X,wherein R₃ represents R₃ as defined above or a group convertible to R₃,in the presence of a suitable catalyst, such as a copper (I) halide anda bivalent or zerovalent palladium compound in the presence of, e.g.,triphenylphosphine, in a suitable solvent, such as an amine, as in theprocedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), provides acompound of the Formula 2-Scheme 1. Compounds of the Formula 1-Scheme 1may be prepared by procedures analogous to those described in co-pendingU.S. patent application Ser. No. 07/862,030 filed 2 Apr. 1992 and itsprogeny U.S. Ser. No. 07/968,762 30 Oct. 1992 and PCT appliation numberPCT/US93/01991 designating the United States as a continuing applicationand filed 5 Mar. 1993. ##STR2##

Alternatively, compounds of the invention wherein Z, X₄ and R₃ representZ, X₄ and R₃ as defined above or a group convertible to Z, X₄ or R₃, maybe prepared from the corresponding ketones as, e.g., compound 1-Scheme2, by the synthetic procedures described in above mentioned U.S. patentapplication Ser. No. 07/862,030 filed 2 Apr. 1992, etc.; syntheses ofsuch ketone starting materials are described in co-pending U.S.application Ser. Nos. 07/862,083 and 07/968,753 and PCT applicationserial number PCT/US93/02045 filed 5 Mar. 1993 (designating the U.S. asa continuation application) now published. ##STR3##

Alternatively, oxidative carbonylation of a terminal acetylene as, e.g.,compound 1-Scheme 3, using an appropriate metal salt, such as a coppersalt with a catalytic amount of a palladium salt, in the presence of asuitable base as an acid trap, such as sodium acetate, in a suitablealcohol, such as methanol, as in the method of Tsuji et al. (Tet. Lett.,1980, 21, 849), then provides the compound of the Formula 2-Scheme 3;such compounds may then be converted to other compounds of the Formula(I) by manipulation of the ketone as described above and by independentmanipulation of the carboxylic ester moiety using standardtransesterification or amidation conditions. Syntheses of such ketonestarting materials are described in the referenced U.S. patentapplications referenced above, i.e., U.S. Ser. No. 07/862,083 and itsprogeny. ##STR4##

Likewise, oxidative carbonylation of a terminal acetylene as, e.g.,compound 1-Scheme 4, wherein Z and X₄ represents Z and X₄ as defined inrelation to Formula (I) or a group convertible to Z or X₄, using anappropriate metal salt, such as a copper salt with a catalytic amount ofa palladium salt, in the presence of a suitable base as an acid trap,such as sodium acetate, in a suitable alcohol, such as methanol, as inthe method of Tsuji et al. (Tet. Lett., 1980, 21, 849), then providesthe compound of the Formula 2-Scheme 4; such compounds may then beconverted to other compounds of the Formula (I) by manipulation of thecarboxylic ester moiety using standard transesterification or amidationconditions. ##STR5##

Preparation of the remaining compounds of the Formula (I) may beaccomplished by procedures analogous to those described above and in theExamples, infra.

It will be recognized that some compounds of the Formula (I) may existin distinct diastereomeric forms possessing distinct physical andbiological properties; such isomers may be separated by standardchromatographic methods.

The following examples are given to illustrate the invention and are notintended to limit it in any fashion. Reference is made to the claims forwhat is reserved to the inventor hereunder.

SYNTHETIC EXAMPLES Example 1 Preparation of Cis-4-(3-Cyclopentyloxy-4-Methoxyphenyl)-4-(4-Pyridylethynyl)Cyclohexane-1-CarboxylicAcid!

1a) cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexane-1-carboxylicacid!

To a suspension of cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanocyclohexanecarboxylic acid! (1.002 g, 2.91 mmol, prepared as describedin co-pending U.S. appliation Ser. No. 07/862,030 filed 2 Apr. 1992 andits progeny U.S. Ser. No. 07/968,762 30 Oct. 1992 and PCT appliationnumber PCT/US93/01991 designating the United States as a continuingapplication and filed 5 Mar. 1993) in toluene (30 mL) at 0° C. under anargon atmosphere was dropwise added over 15 min a 1.0M solution ofdiisobutylaluminum hydride in toluene (6.00 mL, 6.00 mL). The solutionwas stirred for 2 h at room temperature, then was quenched at 0° C. withsaturated ammonium chloride, was diluted with ethyl acetate and 10%hydrochloric acid (50 mL) and was extracted twice with ethyl acetate.The extract was dried (magnesium sulfate) and was evaporated.Purification by flash chromatography, eluting with 5:95methanol/dichloromethane, provided cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexane-1-carboxylicacid! as a white solid. m.p. 137°-139° C. ¹ H-NMR (400 MHz, CDCl₃) δ9.31 (s, 1H), 6.85 (m, 2H), 6.77 (m, 1H), 4.75 (m, 1H), 3.83 (s, 3H),2.58 (br d, J=12 Hz, 2H), 2.35 (m, 1H), 2.09 (m, 2H), 1.8-2.0 (m, 6H),1.5-1.8 (m, 6H).

1b) trans-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane-1-carboxylicacid!

A solution of dimethyl (diazomethyl)phosphonate (0.30 g, 2.0 mmole,prepared as in Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem.1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (2 mL) at -78°C. was added via cannulation to a solution of potassium t-butoxide(0.169 g, 1.50 mmol) dissolved in dry tetrahydrofuran (2 mL) at -78° C.under an argon atmosphere. After 15 min, a solution of cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexane-1-carboxylicacid! (0.173 g, 0.5 mmol) in dry tetrahydrofuran (2 mL) at -78° C. wasadded rapidly. The reaction was allowed to warm gradually to roomtemperature over 1 h and then was stirred for an additional hour. Thereaction was quenched with saturated ammonium chloride, was acidifiedwith 10% hydrochloric acid, was extracted three times withdichloromethane, the extract was dried (magnesium sulfate) and wasevaporated. Purification by flash chromatography, eluting with 3:1 ethylacetate/hexanes, provided trans-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane-1-carboxylicacid! as a white solid. m.p. 152°-153° C. ¹ H-NMR (400 MHz, CDCl₃) δ7.15 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.5, 2.2 Hz, 1H), 6.83 (d, J=8.5 Hz,1H), 4.80 (m, 1H), 3.84 (s, 3H), 2.46 (s, 1H), 2.37 (m, 1H), 2.07 (m,6H). 1.8-2.0 (m, 6H), 1.73 (m, 2H), 1.62 (m, 2H).

1c) cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexane-1-carboxylicacid!

To a solution of trans-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane-1-carboxylicacid! (0.20 g, 0.57 mmol) and 4-bromopyridine (0.91 g, 4.3 mmol) inpiperidine (2 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)-palladium(0) (0.027 g, 4%), copper (I)iodide (0.007 g, 6%) and a small crystal of triphenylphosphine, and themixture was heated at 80°-85° C. for 0.5 h. Ammonium chloride was addedand the mixture was extracted three times with dichloromethane, theextract was dried (magnesium sulfate) and was evaporated. Purificationby successive flash chromatographies, eluting first with 7:93, then with5:95 methanol/dichloromethane, provided cis4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexane-1-carboxylicacid as an off-white solid. mp 183°-184° C. Anal calcd for C₂₆ H₂₉ NO₄·0.35 H₂ O: C, 73.34; H, 7.03; N, 3.29; found: C, 73.21; H, 6.84; N,3.50.

Example 2 Preparation of Cis- Methyl4-(3-Cyclopentyloxy-4-Methoxyphenyl)-4-(4-Pyridylethynyl)Cyclohexane-1-Carboxylate!

2a) cis- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexane-1-carboxylate!

To a suspension of 80% sodium hydride/mineral oil (0.029 g, 0.96 mmol)in hexamethylphosphoramide (1 mL) at room temperature under an argonatmosphere was added dropwise a solution of cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexane-1-carboxylicacid! (0.30 g, 0.87 mmol) in hexamethylphosphoramide (1 mL). After 0.5h, dimethyl sulfate (0.090 mL, 0.96 mmol) was added and stirring wascontinued for an additional hour. The reaction was quenched withsaturated ammonium chloride and was extracted twice with ethyl acetate.The extract was washed three times with water, once with brine, wasdried (magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 2:8 ethyl acetate/hexanes, provided cis-methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexane-1-carboxylate!as a colorless oil. ¹ H-NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 6.84 (m,2H), 6.76 (m, 1H), 4.75 (m, 1H), 3.97 (s, 3H), 3.68 (s, 3H), 2.56 (br d,J=12 5 Hz, 2H), 2.30 (m, 1H), 1.8-2.0 (m, 10H), 1.5-1.7 (m, 4H).

2b) trans- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane-1-carboxylate!

A solution of dimethyl (diazomethyl)phosphonate (0.407 g, 2.71 mmole,prepared as in Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem.1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (4 mL) at -78°C. was added via cannulation to a solution of potassium t-butoxide(0.344 g, 3.06 mmol) dissolved in dry tetrahydrofuran (4 mL) at -78° C.under an argon atmosphere. After 15 min, a solution of cis- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexane-1-carboxylate!(0.552 g, 1.53 mmol) in dry tetrahydrofuran (4 mL) at -78° C. was addedrapidly. The reaction was allowed to warm gradually to room temperatureover 1 h and was stirred for an additional hour. The reaction wasquenched with saturated ammonium chloride, was extracted three timeswith dichloromethane, the extract was dried (magnesium sulfate) and wasevaporated. Purification by flash chromatography, eluting with 1:9 ethylacetate/hexanes, provided trans- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane-1-carboxylate!as a colorless oil. ¹ H-NMR (400 MHz, CDCl₃) δ 7.14 (d, J=2.1 Hz, 1H),7.04 (dd, J=8.4, 2.1 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.80 (m, 1H), 3.84(s, 3H), 3.71 (s, 3H), 2.45 (s, 1H), 2.33 (m, 1H), 1.8-2.1 (m, 12H),1.70 (m, 2H), 1.56 (m, 2H).

2c) cis- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexane-1-carboxylate!

To a solution of trans- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexanecarboxylate!(0.13 g, 0.37 mmol) and 4-bromopyridine (0.59 g, 3.7 mmol) in piperidine(2 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)-palladium(0) (0.017 g, 4%), copper (I)iodide (0.004 g, 6%) and a small crystal of triphenylphosphine, and themixture was heated at 80°-85° C. for 0.5 h. Ammonium chloride was addedand the mixture was extracted three times with dichloromethane, theextract was dried (magnesium sulfate) and was evaporated. Purificationby flash chromatography, eluting with 1:3 ethyl acetate/hexanes,provided cis- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-cyclohexanecarboxylate! as acolorless oil. Anal calcd for C₂₇ H₃₁ NO₄ ·0.25 H₂ O: C74.03, H 7.25, N 3.20; found: C 73.78, H 7.14, N 3.20. ¹ H-NMR (400 MHz,CDCl₃) δ 8.6 (br, 2H), 7.4 (m, 2H), 7.05 (d, J=2 Hz, 1H), 7.04 (dd, J=8,2 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 4.8 (m, 1H), 3.85 (s, 3H), 3.72 (s,3H), 2.4 (m, 1H), 2.1 (m, 6H), 1.8-2.0 (m, 8H), 1.6 (m, 2H).

Example 3 Preparation of Cis- Methyl4-(3-Cyclopentyloxy-4-Methoxyphenyl)-4-(Phenylethynyl)Cyclohexane-1-Carboxylate!

To a solution of trans- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane-1-carboxylate!(0.19 g, 0.54 mmol) and iodobenzene (0.61 mL, 5.4 mmol) in piperidine (3mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)-palladium(0) (0.026 g, 4%), copper (I)iodide (0.007 g, 6%) and a small crystal of triphenylphosphine, and themixture was heated at 80°-85° C. for 1 h. The reaction was diluted withdichloromethane, was washed with 1N hydrochloric acid, was dried(magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 1:9 ethyl acetate/hexanes, provided cis-methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(phenylethynyl)cyclohexane-1-carboxylate!as a dark orange oil. ¹ H-NMR (400 MHz, CDCl₃) δ 7.46 (m, 2H), 7.30 (m,3H), 7.22 (d, J=2.2 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz,1H), 4.81 (m, 1H), 3.84 (s, 3H), 3.71 (m, 3H), 2.38 (m, 1H), 2.0-2.2 (m,6H), 1.93 (m, 4H), 1.7-1.9 (m, 4H), 1.6 (m, 2H).

Example 4 Preparation of Cis-4-(3-Cyclopentyloxy-4-Methoxyphenyl)-4-(Phenylethynyl)Cyclohexane-1-Carboxylic Acid!

A solution of cis- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(phenylethynyl)-cyclohexane-1-carboxylate!(0.160 g, 0.37 mmol) and lithium hydroxide monohydrate (0.044 g, 1.11mmol) in methanol (2.5 mL) in a sealed tube was heated at 80°-85° C. for8 h. The reaction was acidified with 10% hydrochloric acid, and was thenextracted three times with dichloromethane. The extract was dried(magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 3:97 methanol/dichloromethane, providedcis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(phenylethynyl)cyclohexane-1-carboxylicacid! as a white solid. mp 133°-134° C. ¹ H-NMR (400 MHz, CDCl₃) δ 7.47(m, 2H), 7.30 (m, 3H), 7.23 (s, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.85 (d,J=8.5 Hz, 1H), 4.83 (m, 1H), 3.85 (s, 3H), 2.42 (m, 1H), 2.0-2.0 (m,8H), 1.7-2.0 (m, 6H), 1.6 (m, 2H). Anal. (C₂₇ H₃₀ O₄) calcd: C, 77.48;H, 7.23; found: C, 77.09; H, 7.22.

Example 5 Preparation of Cis- Methyl4-(3-Cyclopentyloxy-4-Methoxyphenyl)-4-(2-Pyridylethynyl)Cyclohexane-1-Carboxylate!

To a solution of trans- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane-1-carboxylate!(0.12 g, 0.35 mmol) and 2-bromopyridine (0.335 mL, 3.5 mmol) inpiperidine (1.5 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)-palladium(0) (0.017 g, 4%), copper (I)iodide (0.004 g, 6%) and a small crystal of triphenylphosphine and themixture was heated at 80°-85° C. for 0.5 h. Ammonium chloride was added,the mixture was extracted three times with dichloromethane, the extractwas dried (magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 3:7 ethyl acetate/hexanes, provided cis-methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)-cyclohexane-1-carboxylateas a yellow oil!. ¹ H-NMR (400 MHz, CDCl₃) δ 8.58 (d, J=4.8 Hz, 1H),7.65 (m, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.22 (m, 1H), 7.18 (d, J=2.1 Hz,1H), 7.13 (dd, J=8.5, 2.3 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.81 (m, 1H),3.84 (s, 3H), 3.70 (s, 3H), 2.40 (m, 1H), 2.0-2.2 (m, 6H), 1.7-2.0 (m,8H), 1.6 (m, 2H).

Example 6 Preparation of Cis-4-(3-Cyclopentyloxy-4-Methoxyphenyl)-4-(2-Pyridylethynyl)Cyclohexane-1-CarboxylicAcid!

A solution of cis- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexane-1-carboxylate!(0.126 g, 0.29 mmol) and lithium hydroxide monohydrate (0.035 g, 0.87mmol) in methanol (2.5 mL) in a sealed tube was heated at 80°-85° C. for20 h. The reaction was acidified with 1N hydrochloric acid and wasextracted with three times dichloromethane. The extract was dried(magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 7:93 methanol/dichloromethane, providedcis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexane-1-carboxylicacid! as a white solid. mp 169°-170° C. ¹ H-NMR (400 MHz, CDCl₃) δ 8.69(d, J=5 Hz, 1H), 7.70 (t, J=8 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.26 (m,1H), 7.17 (d, J=2 Hz, 1H), 7.12 (dd, J=8.4, 2 Hz, 1H), 6.85 (d, J=8.5Hz, 1H), 4.81 (m, 1H), 3.85 (s, 3H), 2.38 (m, 1H), 2.21 (m, 6H), 1.92(m, 4H), 1.82 (m, 4H), 1.59 (m, 2H).

Example 7

Using the methods, reagents, etc., set forth is the preceeding examples,and substituting the appropriate substrates or intermediates, thefollowing compounds are prepared:

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-methyl1,2,4!oxadiazol-3-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(3-methyl1,2,4!oxadiazol-5-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-methyl1,3,4!oxadiazol-2-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-methyl1,3,4!thiadiazol-2-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-trifluoromethyl1,2,4!oxadiazol-3-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(3-trifluoromethyl1,2,4!oxadiazol-5-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-trifluoromethyl1,3,4!oxadiazol-2-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-trifluoromethyl1,3,4!thiadiazol-2-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-2-aminopyrimidin-5-yl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-2-acetamidopyrimidin-5-yl!ethynyl)cyclohexan-1-carboxylic acid!,

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-2,6-dimethylpyridin-4-yl!ethynyl)cyclohexan-1-carboxylic acid!, and

cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-2,6-dimethylpyridin-3-yl!ethynyl)cyclohexan-1-carboxylic acid!.

Pharmaceutically acceptable salts can be prepared from these acids usingwell known salt-forming chemistries, and as described and referencedabove.

UTILITY EXAMPLES EXAMPLE A Inhibitory Effect of Compounds of Formulas(Ia) or (Ib) on In Vitro TNF Production by Human Monocytes

The inhibitory effect of compounds of Formulas (Ia) or (Ib) on in vitroTNF production by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

EXAMPLE B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of Formulas (Ia) or (Ib). The protocolused in these models is described in Badger et al., EPO publishedApplication 0 411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec.27, 1990.

The compound of Example 1 herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

EXAMPLE C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of Formulas (Ia) or (Ib) can be determined using a battery offive distinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III arepartially purified using standard chromatographic techniques Torphy andCieslinski, Mol. Pharnacol., 37:206-214, 1990!. PDE IV is purified tokinetic homogeneity by the sequential use of anion-exchange followed byheparin-Sepharose chromatography Torphy et al., J. Biol. Chem.,267:1798-1804, 1992!.

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC₅₀'s in the nanomolar to μM range for compounds of the workings examplesdescribed herein for Formula (I) have been demonstrated.

What is claimed is:
 1. A compound of the Formula (Ia) and (Ib): ##STR6##wherein: R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n)C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄R₅)_(r) R₆ wherein the alkyl moieties unsubstituted or substituted withone or more halogens;m is0 to 2; n is 0 to 4; r is 0 to 6; R₄ and R₅ areindependently selected hydrogen or C₁₋₂ alkyl; R₆ is hydrogen, methyl,hydroxyl, aryl, halo substituted aryl, aryloxyC₁₋₃ alkyl, halosubstituted aryloxyC₁₋₃ alkyl, indanyl, indenyl, C₇₋₁₁ polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl,tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted orsubstituted by 1 to 3 methyl groups, one ethyl group, or an hydroxylgroup; provided that: a) when R₆ is hydroxyl, then m is 2; or b) when R₆is hydroxyl, then r is 2 to 6; or c) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then m is 1 or 2; or d) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then r is 1 to 6; e) when n is 1 and m is 0, then R₆ is other than H in--(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆ ; X is YR₂, fluorine, NR₄ R₅, or formylamine; Y is O or S(O)_(m) ', m is 0, 1, or 2; X₂ is O or NR₈ ; X₃ ishydrogen or X; X₄ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈R₈ ; R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens; s is 0 to 4; W is alkyl of 2 to 6carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbonatoms; R₃ is COOR₁₄, C(O)NR₄ R₁₄ or R₇ ; Z is C(Y')R₁₄, C(O)OR₁₄,C(Y')NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN, C(NOR₈)R₁₄, C(O)NR₈ NR₈ C(O)R₈,C(O)NR₈ NR₁₀ R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀ R₁₄, C(NR₁₄)NR₈ R₈, C(NCN)NR₁₀R₁₄, C(NCN)SR₉, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 4- or5-triazolyl 1,2,3!, 3- or 5-triazolyl 1,2,4!, 5-tetrazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-oxadiazolyl 1,2,4!),2-oxadiazolyl 1,3,4!, 2-thiadiazolyl 1,3,4!, 2-, 4-, or 5-thiazolyl, 2-,4-, or 5-oxazolidinyl, 2-, 4-, or 5-thiazolidinyl, or 2-, 4-, or5-imidazolidinyl; wherein all of the heterocylic ring systems areunsubstituted or substituted one or more times by R₁₄ ; Y' is O or S; R₇is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkyl groupis unsubstituted or substituted one or more times by methyl or ethylunsubstituted or substituted by 1-3 fluorines, --Br, --Cl, --NO₂, --NR₁₀R₁₁, --C(O)R₈, --CO₂ R₈, --O(CH₂)_(q) R₈, --O(CH₂)₂₋₄ OR₈, --CN,--C(O)NR₁₀ R₁₁, --O(CH₂)_(q) C(O)NR₁₀ R₁₁, --O(CH₂)_(q) C(O)R₉, --NR₁₀C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃,--C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁, --C(NCN)SR₉, --NR₁₀ C(NCN)SR₉,--NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉, --S(O)_(m) 'R₉, --NR₁₀C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, or R₁₃ ; q is 0, 1, or 2; R₁₂ isR₁₃, C₃ -C₇ cycloalkyl, or an unsubstituted or substituted aryl orheteroaryl group selected from the group consisting of 2-, 3- or4-pyridyl, pyrimidyl, pyrazolyl, 1- or 2-imidazolyl, pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, 2- or 3-thienyl,quinolinyl, naphthyl, and phenyl; R₈ is independently selected fromhydrogen or R₉ ; R₉ is C₁₋₄ alkyl optionally substituted by one to threefluorines; R₁₀ is OR₈ or R₁₁ ; R₁₁ is hydrogen, or C₁₋₄ alkylunsubstituted or substituted by one to three fluorines;or when R₁₀ andR₁₁ are as NR₁₀ R₁₁ they may together with the nitrogen form a 5 to 7membered ring comprised of carbon or carbon and one or more additionalheteroatoms selected from O, N, or S; R₁₃ is a substituted orunsubstituted heteroaryl group selected from the group consisting ofoxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl,imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, andthiadiazolyl, and where R₁₃ is substituted on R₁₂ or R₁₃ the rings areconnected through a carbon atom and each second R₁₃ ring may beunsubstituted or substituted by one or two C₁₋₂ alkyl groupsunsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R₁₄is hydrogen or R₇ ; or when R₈ and R₁₄ are as NR₈ R₁₄ they may togetherwith the nitrogen form a 5 to 7 membered ring comprised of carbon orcarbon and one or more additional heteroatoms selected from O, N, or S;provided that: (f) R₇ is not C₁₋₄ alkyl optionally substituted by one tothree fluorines; or the pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 wherein R₁ is --CH₂ -- cyclopropyl, --CH₂--C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl unsubstituted or substituted by OH,tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or --C₁₋₂ alkylunsubstituted or substituted by 1 or more fluorines, and --(CH₂)₂₋₄ OH;R₂ is methyl or fluoro-substituted alkyl, W is ethynyl or1,3-butadiynyl; R₃ is R₇ where R₇ is an unsubstituted or substitutedaryl or heteroaryl ring, X is YR₂, and Z is C(O)OR₁₄.
 3. A compoundaccording to claim 2 wherein R₁ is --CH₂ -cyclopropyl, cyclopentyl,3-hydroxycyclopentyl, methyl or CF₂ F; X is YR₂ ; Y is oxygen; X₂ isoxygen; X₃ is hydrogen; and R₂ is CF₂ F or methyl, W is ethynyl or1,3-butadiynyl, and R₃ is a substituted or unsubstituted pyrimidinylring.
 4. A compound according to claim 1 which iscis- methyl4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridyl)ethynyl!cyclohexan-1-carboxylate!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridyl)ethynyl!cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridyl)ethynyl!cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(phenylethynyl)cyclohexan-1-carboxylicacid!, cis- 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-methyl1,2,4!oxadiazol-3-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(3-methyl1,2,4!oxadiazol-5-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-methyl1,3,4!oxadiazol-2-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-methyl1,3,4!thiadiazol-2-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-trifluoromethyl1,2,4!oxadiazol-3-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(3-trifluoromethyl1,2,4!oxadiazol-5-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-trifluoromethyl1,3,4!oxadiazol-2-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2- 3-(5-trifluoromethyl1,3,4!thiadiazol-2-yl)phenyl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-2-aminopyrimidin-5-yl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-2-acetamidopyrimidin-5-yl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-2,6-dimethylpyridin-4-yl!ethynyl)cyclohexan-1-carboxylic acid!, cis-4-(3-cyclopentyloxy-4methoxyphenyl)-4-(2-2,6-dimethylpyridin-3-yl!ethynyl)cyclohexan-1-carboxylic acid!, or apharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising a compound according to Formula (Ia) or (Ib) asin claim 1 and a pharmaceutically acceptable excipient.
 6. A method fortreating asthma comprising administering to a mammal in need thereof acompound of Formula (Ia) or (Ib) according to claim 1 alone or inadmixture with a pharmaceutically acceptable excipient.